Physiological method of improving vision

ABSTRACT

The present invention is directed to a physiological method for improving vision in a human patient. This method involves topical application to the eye, an amount of acetylcholine esterase inhibitor containing composition so that it is sufficient to provide a therapeutic benefit to improve the visual acuity in the human patient. The composition is administered topically and at bedtime after an eye straining work for about 20 minutes. The method disclosed herein is used for treatment and prevention of congenital and acquired color vision blindness, treatment of ocular hypertension and glaucoma, prevention of the progression of myopia, treatment of strabismus or squint, potentiation of best visual acuity, neuro-protection, treatment of aberrations secondary to pupil dilation.

This application claims the benefit of the continuation of U.S.application Ser. No. 09/667,270 filed Sep. 22, 2000 now U.S. Pat. No.6,273,092, and U.S. application Ser. No. 09/773,878 filed Jan. 31, 2001which applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a newly identified pharmacologicaltreatment to treat age related diseases or disorders of the both theanterior and posterior segment of the eye or to potentiate best visualacuity. Specifically, the invention provides methods for treatment andprevention of congenital and acquired color vision blindness, treatmentof ocular hypertension and glaucoma, prevention of the progression ofmyopia, treatment of strabismus or squint, potentiation of best visualacuity, neuro-protection, treatment of aberrations secondary to pupildilation by topical administration of acetylcholine esterase inhibitors.

BACKGROUND OF THE INVENTION

The image of an infinite distant object will fall in front of the retinain myopia (nearsightedness) on the retina in emmetropia (normalsightedness) and behind the retina in hyperopia (farsightedness), whenthese eyes are exerting zero accommodation. The emmetropic eye formssharp retinal imagers of distant objects with the lens of the eye inrelaxed accommodation. This ideal optical human condition of emmetropiais possible as a result of a function of corneal curvature and axiallength of the eye and takes into account that parallel rays of lighttravel from air will bend when passing through the cornea surface andinto the liquid environment of the eye. Normally, the emmetrope can seedistant scenes sharply and, in addition, can see objects held close tothe eye without awareness of any focusing by the eye. The process offocusing upon a near object, called accommodation, is accomplished bythe muscles of the ciliary body of the eye contracting to vary the shapeof the crystalline lens of the eye. To see at a distance, the ciliarymuscles are relaxed; to see nearby, the ciliary body contracts toreshape the lens. The amount of accommodation exerted from the relaxedstate of the muscles of the ciliary body to the contracted state of theciliary muscles (i.e., to full accommodation) of the eye is termed theamplitude of accommodation. When the eye is fully accommodated, thepoint in space which is focused upon the retina is called the near pointof the eye, or the nearest point of distinct vision.

Accommodation is measured in diopters. A diopter is defined as 1/thedistance in meters to the near point of vision. In both emmetropicindividuals and myopic individuals, who have been treated by cornealsurgery, the ability to accommodate is gradually lost with age. In fact,the ability to reshape the lens to focus upon a near point may becompletely lost after age 40 years. This decrease in the amplitude ofaccommodation and the consequent loss of near vision is calledpresbyopia and is thought to be a normal part of the aging process. Theinverse relationship between age and the amplitude of accommodation canbe seen in Table 1.

TABLE 1 Relationship Between Age, Amplitude of Accommodation and NearVision for Emmetrope Amplitude of Near Point Accommodation For EmmetropeAge (Diopters) (cm) 10 14.0 7.0 20 10.0 10.0 30 7.0 14.2 40 4.5 22.2 453.5 28.5 50 2.5 40.0 55 1.75 57.0 60 1.00 100.0 65 0.50 200.0 70 0.25400.0 0

Physiologically, accommodation is under the influence of theparasympathetic nervous system and occurs through the chemical action ofacetycholine on muscle fibers of the ciliary body. Contraction of theciliary body muscles decreases the tension of the lens ligaments, whichallows the lens to focus at near point.

Acetylcholine, when working on the eye or other smooth muscles of thebody is regulated by cholinesterase enzyme which breaks downacetylcholine and thus turns off its parasympathetic effect on muscles.In an effort to correct presbyopia, the effect of acetylcholine on themuscles of the eye could be increased either by adding an acetylcholinelike drug such as pilocarpine, or by blocking the breakdown ofacetylcholine with a drug which inhibits the natural cholinesterase(e.g., a cholinesterase inhibitor).

There have been problems with the first approach; When pilocarpinehydrochloride, an acetylcholine like drug, sold as SALAGER® (MGI Pharma,Minnetonka, Minn.), is applied to an emmetropic eye, the increasedparasymathetic effect leads to enhanced near vision but at the sacrificeof distant vision. The emmetropic eye becomes myopic as a consequence ofthis adverse side effect acetylcholine treatment to correct presbyopiahas not been effective. Likewise, the second approach, the use ofcholinesterase inhibitors, has been unsuccessful because of similar sideeffects from the cholinesterase drugs used in current concentrations. Noother pharmacological agents have been found to restore near vision inan individual with presbyopia. Thus presbyopia is considered untreatablewith current pharmacological agents.

A diminished visual acuity or total loss of vision may result from anumber of eye diseases or disorders caused by dysfunction of tissues orstructures in the anterior region of the eye and/or posterior region ofthe eye. The eye is divided anatomically into an anterior and posteriorsegment. The anterior segment includes the cornea, anterior chamber,iris and ciliary body (anterior choroid), posterior chamber andcrystalline lens. The posterior segment includes the retina with opticnerve, choroid (posterior choroid) and vitreous. Some of the examples ofeye disorders resulting from the pathologic conditions of structures inthe anterior segment of the eye are dry eye syndrome, keratitis orcorneal dystrophy, cataracts, and glaucoma. The disease or disorders ofthe posterior segment of the eye in general are retinal or choroidalvascular diseases or hereditary diseases such as Lebers CongenitalAmaurosis. The posterior portion of the eyeball supports the retina,choroid and associated tissues.

So far certain treatments, including the topical application ofacetylcholine esterase (AChE) inhibitor, have been used with somesuccess to treat ophthalmic disorders caused by dysfunction of eyemuscles in the anterior region of the eye. Acetylcholine, when workingon the eye or other smooth muscles of the body is regulated by thenatural cholinesterase enzyme which breaks down acetylcholine and thusturns off its parasympathetic effect on muscles. The effect ofacetylcholine on the muscles of the eye could be increased either byadding an acetylcholine like drug such as pilocarpine, or by blockingthe breakdown of acetylcholine with an AChE drug which inhibits thenatural cholinesterase (e.g., a cholinesterase inhibitor). However, theadministration of acetylcholine (pilocarpine) results in the side effectof nearsightedness, thus acetylcholine treatment to correct presbyopiahas not been effective.

A diminished visual activity may result due to pathologic conditions oftissues or structures located n the anterior segment of the eye or inthe posterior region of the eye. Age related macular degeneration (AMD)is one of the specific diseases associated with the posterior portion ofthe eyeball and is the leading cause of blindness among older people.AMD results in damage to the macula, a small circular area in the centerof the retina. Because the macular is the area which enables one todiscern small details and to read or drive, its deterioration may bringabout diminished visual acuity and even blindness. The retina containstwo forms of light receiving cells, rods and cones, that change lightinto electrical signals. The brain then converts these signals into theimages that we see. The macula is rich in cone cells, which give us ourcentral vision. People with AMD suffer deterioration of central visionbut usually retain peripheral sight.

There are several types of AMD. The “dry” (non-exudative) type accountsfor about 90% of AMD cases. The wet (exudative) form afflicts only about10% of AMD patients. However, the wet form is a more serious diseasethan the dry form and is responsible for about 90% of the instances ofprofound visual loss resulting from the disease. Wet AMD often startsabruptly with the development of tiny, abnormal, leaky blood vesselstermed CNVs (chorodial new vessels), directly under the macula. In mostpatients, this leads to scarring and severe central vision loss,including distortion, blind spots, and functional blindness.

Signs of AMD such as drusen, which are abnormal yellow deposits underthe retina, can be present even in patient with normal vision. Drusenlook like specks of yellowish material under the retina. They aredeposits of extracellular material that accumulate between retinalpigment epithelium (RPE) and Bruch's Membrane. The RPE is a specializedcell layer that ingests used-up outer tips of the rod and cone cells andprovides them with essential nutrients (e.g. vitamin A derivatives).Bruch's membrane is a noncellular structure (made mostly of collagen)that separates the RPE from the choroidal circulation below. Thechoroidal circulation provides the blood supply to the rods, cones andRPE cells. A few small drusen normally form in the human eye, usuallyafter age 40. AMD, in contrast, is almost always associated with abuild-up of additional drusen. Drusen occur in two forms. Hard drusenare small, solid deposits that apparently do no harm when present insmall numbers. Soft drusen are larger and may have indistinct borders.As soft drusen build up between the RPE and Bruch's membrane, they liftup the RPE and force the two layers apart.

Drusen develop long before the abnormal vessels of wet AMD. Threecharacteristics of soft drusen are risk factors for developing CNV: Thepresence of five or more drusen deposits; drusen size greater than 63micrometers (about the thickness of a human hair); and, the clumping ofthe drusen deposits. Some evidence suggests soft drusen are instrumentalin the spread of abnormal vessels, but whether they stimulate vesselgrowth (angiogenesis) or simply provide space for them by lifting up theRPE remains unclear.

Two networks of blood vessels nourish the retina, one located on theretinal surface and the other located deep in the retina, external toBruch's membrane. The abnormal vessels of AMD originate in the lowernetwork of vessels, called the choroidal circulation. These vessels maketheir way through Bruch's membrane and spread out under the RPE. Bloodand fluids leak from them and cause the photoreceptor cells todegenerate and the macula to detach from the cells under it.

Slightly blurred or distorted vision is the most common early symptom ofAMD. Visual loss with dry AMD usually progresses slowly while visualloss with wet AMD proceeds more rapidly and may occur over days orweeks. Patients who have wet AMD in one eye are at increased risk ofdeveloping CNVs in the other eye. The magnitude of the risk varies,depending on the appearance of the second eye. The risk is greater ineyes with numerous large drusen, with abnormal pigment changes in themacula, and in patients with a history of high blood pressure.

Presently, there are no effective treatments available for visuallydisabling retinal vascular disease or choroidal vascular disease such asdiabetic retinopathy and age related macular degeneration (AMD). Thetherapeutic strategies for treating diminished or loss of vision causedby the vascular eye diseases vary. Laser photocoagulation is the firsteffective treatment found for wet AMD. The laser destroys abnormal bloodvessels beneath the retinal and seals leaky areas but also destroys theoverlying retina. This treatment can inhibit wet AMD's progression, butit cannot restore lost vision and the disease often progresses despitelaser therapy. The use of the drug Visudyne (veteporfin) is anotherapproach to treat AMD. This drug belongs to a class of drugs used inphotodynamic therapy (PDT), a technique in which light-activated dyesdestroy tissue. After an injection, the light-sensitive drug tends tolocalize in the new choroidal vessels. A low-intensity laser is thenfocused on the dye-containing CNVs, triggering a chemical reaction thatdestroys the abnormal vessels. The drug can stabilize vision for a timeand slow retinal damage. Other PDT drugs for AMD are currently inclinical testing. However, even with the availability of PDT andconventional laser treatment, patients with the vascular diseases of theeye still have no known effective treatment option and remain vulnerableto sustaining permanent damage to the retinal cells.

The other retinal or choroidal vascular diseases include but not limitedto macular cyst, macular hole, solar retinopathy, diabetic retinopathy,branch retinal vein occlusion.

Hitherto it has not been known that a particular regimen of the topicaladministration of AChE inhibitor can arrest or alleviate thedeterioration of vision associated with retinal or choroidal disordersresulting from the pathological conditions of tissues or structureslocated in the posterior region of the eye. It has also not been knownthat a particular regimen of the topical administration of AChEinhibitor can be used for the Treatment and Prevention Congenital andAcquired Color Vision Blindness, Treatment of Ocular Hypertension andGlaucoma, Prevention of the Progression of Myopia, Treatment ofStrabismus or Squint, Potentiation of Best Visual Acuity, achievingNeuro-protection and for treatment of Aberrations Secondary to PupilDilation.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery ofindirectly improving endogenous acetylcholine levels of eye withoutadverse effects by using an acetylycholine esterase inhibitor (AChEinhibitor). The method disclosed herein is a physiological methodwithout any need for surgery or laser treatment. The methods use thetopical application of acetylcholine esterase inhibitors in very lowconcentrations but sufficient enough to effectively restore the visualacuity. Specifically, the present invention provides methods for, amongother things, the treatment and prevention congenital and acquired colorvision blindness, treatment of ocular hypertension and glaucoma,prevention of the progression of myopia, treatment of strabismus orsquint, potentiation of best visual acuity, achieving neuro-protectionand for correcting aberrations secondary to pupil dilation by topicaladministration of acetylcholine esterase inhibitors in a concentrationeffective to improve eye vision in humans without any adverse sideeffects. Therefore, this invention provides several advantages overprior art methods employed for achieving the same.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to methods for restoring lost reading or nearvision and increasing the amplitude of accommodation in presbyopicpatients with emmetropic eyes. The method involves the topicalapplication of an acetylcholine esterase (AChE) inhibitor to thepatient. The method can improve near vision without any side effect suchas blurring, loss of distant vision or induction of myopia. Themedication, applied in appropriate concentration, will allow the patientto achieve near vision, without corrective lenses, which will lastseveral days. Moreover, unlike corrective reading glasses, because ofthe increase in amplitude of accommodation by practicing the presentinvention, the individual will be able to focus at many differentlengths between the near point and the distant vision. This eliminatesthe need for bending the head in order to bring an object in line withthe lenses of the reading glasses. For the emmetrope, the presentinvention eliminates for several days the need for corrective readingglasses. For the myopic or hyperopic individual, the present inventioneliminates the need for bifocal lenses.

Acetylcholine esterase inhibitors are known to one skilled in the art.There are at least two AChE inhibitor drugs currently approved forclinical use on the eye in the United States. They are (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate sold asPHOSPOHLINE IODIDE® (Wyeth-Ayerst, Philadelphia, Pa.), and physostigmine(also known as eserine) sold as ANTILIRIUM® (Forest Pharmaceuticals, St.Louis, Mo.). PHOSPHOLINE IODIDE is dispensed as eyedrops at a desiredpotency. PHOSPHOLINE IODIDE of various concentrations, such as forexample 0.25%, 0.125%, 0.06% and 0.03% and a pharmaceutically acceptablesterile diluent to dilute the concentrated form of this drug arecommercially available. PHOSPHOLINE IODIDE is currently used forglaucoma and accommodative esotropia but there has been no successfuluse of this drug for presbyopia because of many adverse side effects ofthe drug especially when used in the standard doses established forglaucoma and accommodative esotropia. As such, PHOSPHOLINE IODIDE is nota preferred drug even to treat glaucoma and accommodative esotropiabecause of many adverse side effects caused by this drug when it is usedin the current regimen of multiple times a day at high concentrations.Some of the side effects known to be caused by the currently recommendeddoses of this drug (for glaucoma at 0.12 and 0.25 BID) are iris cysts,cataract formation especially anterior subcapsular, posterior syneclialand elevated intraocular pressure.

In the new method the cholinesterase inhibitor, such as phospholineiodide, administered in concentrations many fold more dilute thancurrently available pharmacological preparations, applied to the eyebefore sleep will achieve a restoration of the ability to accommodatewith none of the unacceptable side effects of the usual pharmacologicalpreparations and without the loss of distance vision. The effect of oneadministration at night can last for many days and replace the need forcorrective reading lenses during that time. The present invention showsthat the effective concentration of AChE inhibitor in the composition totreat presbyopia can be very low (for example, as low as at least 0.005%to about 0.0075% of PHOSPHOLINE IODIDE) to be effective. The inventiondiscloses that such a concentration is extremely useful medically.Specifically, this lower dose range is especially useful in providingeye drugs that will contain a concentration of AChE inhibitor that islow enough to be both safe and effective.

The composition administered to the eye should have a pharmaceuticallyacceptable carrier and a selected AChE inhibitor suspended or dissolvedin the carrier. The concentration of AChE inhibitor in the compositionadministered to the eye and made of administration of the composition inaccordance with this invention depends on the type of AChE inhibitorcontaining composition used for therapy. For example, preferredconcentrations of PHOSPHOLINE IODIDE in the PHOSPHOLINE IODIDEcontaining composition are from about 0.1% to about 0.0019%. Still morepreferred concentrations are from about 0.14% to about 0.00375%. Morepreferred PHOSPHOLINE IODIDE concentrations are from about 0.15% toabout 0.005%. Most preferred PHOSPHOLINE IODIDE concentrations are0.12%, 0.03% and 0.0075%. It is preferred to apply PHOSPHOLINE IODIDEtopically to the eyes in the form of eyedrops. Although it is preferredthat these solutions with various concentrations of PHOSPHOLINE IODIDEare stored in a refrigerator, they an be stored at room temperature forabout two months or even beyond two months without losing their efficacyto restore near vision in presbyopic patients.

A solution containing chlorobutanol (0.55%), mannitol (1.2%) boric acid(0.6%) and exsiccated sodium phosphate (0.026%) can be used as a carriersolution and/or as a diluent for PHOSPHOLINE IODIDE. While this solutionis presently sold as a diluent in the kit containing PHOSPHOLINE IODIDE,other pharmaceutically acceptable carriers or excipients that are knownto enhance membrane permeability and cellular uptake of the drug can beused with or without modification for application to the eye. Suchcarriers are known to one skilled in the art.

For the method of the invention to be effective, it is believed that theAChE inhibitor should be administered in such a way that it reacheslevels in the eye or ciliary muscle sufficient to improve accommodation.Keeping the eyes such aids in this respect and in a preferred embodimentof the invention, the AChE inhibitors is administered at bedtime. Asingle topical application of a given AChE inhibitor at bedtime canenhance the strength of the ciliary body muscle and significantlyimprove the uncorrected near visual acuity in the phakic emmetropicpatient for a few days. For example, application of one to two drops ofPHOSPHOLINE IODIDE of a selected concentration at bedtime can restorereading vision in presbyopic patients for at least five days.Preferably, the following steps are followed every time AChE inhibitoris applied to the patient. The first step is to read for about 30minutes. The second step is to administer an AChE inhibitor of aselected concentration. The third step is to sleep. Without wishing tobe bound by any theory or explanation, it is believed that the readingfor about 30 minutes preconditions eye muscles to respond better to theAChE inhibitor treatments. It takes about 6 to 8 hours of sleep tonotice the restoration. If one is awaked in the middle of the sleep, theindividual may notice partial effect but after 6 to 8 hours of sleep theeffect will be maximized. By the term “bedtime” it is meant that thetime when the patient goes to sleep for about 6 to 8 hours, regardlessof whether it is during the day or night time.

AChE inhibitor can be administered either to the dominant and/or thenon-dominant eye. It is known that usually one eye is “dominant” withrespect to the other and with both eyes open the image from the dominanteye will be perceived more than the non-dominant eye. To show that therestoration of near vision is the result of the effect of AChE inhibitorand not because of subjectivity of the dominant eye being preferred overthe non-dominant eye, one can treat the weaker or non-dominant eye. Bytreating the weaker or non-dominant eye, one can show that the weakereye becomes stronger than the dominant eye in every treated patient andthat the restoration of near vision by AChE inhibitor is real, notbecause of the dominant eye. Also by treating only one eye, the patientcan see the improvement and can judge when to apply another dose (within7-10 days after the first dose) as the non-dominant eye reverts towardseeing like the dominant eye. Additionally, this allows to check for anyside effects and making comparison to the untreated eye.

It should be noted that the method of this invention can be successfullyused to correct presbyopia in patients having emmetropic eyes with anormal crystalline lens. The method can also enhance the near vision ofan individual who has the normal crystalline lens, but has no iris.However, the method may not be successful to correct presbyopia inpresbyopic patients with artificial and rigid intraocular lenses(IOL's). IOL's are inserted at the time of cataract surgery and inrefractive procedures to make an individual emmetropic.

Accordingly, by practicing the present invention, the near point ofdistinct vision and also amplitude of accommodation of emmetropic eyecan be increased by a single topical application. The near point of anemmetrope can be calibrated into amplitude of accommodation (by theformula D=1/distance in meters to the near point of vision). Increase inamplitude of accommodation can be measured by techniques well known tothose skilled in the art. In other words, a suitable dose of AChEinhibitor administered at bedtime can allow the eye to accumulatesufficient stockpiles of acetylcholine by inhibiting acetylcholineesterase activity in the eye and strengthen the ciliary body leading tothe improvement in the near point of distinct vision and amplitude ofaccommodation for sometime. Most middle age emmetropes with presbyopiahave near points at arms length (i.e., they can see the near print, onlyif they move it further and further away from the eye). Reading distanceis generally considered to be 33 cm to 35 cm; arms length is greaterthan this distance. By practicing the method of the present invention, amiddle age patient with 20/70 vision at arms length after treatment withAChE inhibitor can obtain 20/20 vision at 12 inches for over five days.To sustain this 20/20 vision at 12 inches beyond this period, thetreatment can be repeated in the same fashion. Moreover, by practicingthe method of the invention, the restoration of near vision can beachieved in myopes and hyperopic presbyopes who have their distantemmotropic correction with glasses or contact lenses. It eliminates theneed for bifocal glasses.

While the detailed discussion of the treatment methods for restoringreading vision in patients suffering from presbyopia disorder has beenprovided in the text above, the same methods and the concentrations ofAChE inhibitor in the compositions described above can also be used totreat other eye disorders as described in the paragraphs below.

The method of the present invention also provides a method for treatmentand prevention of dry eye syndrome. The dry eye problem is due to lackof certain components in human tears and is known to those skilled inthe art. In dry eye syndrome the tears evaporate too quickly and thepatients need supplements of lubricating drops (artificial tears). Therehas been described treatment of patients with dry eye syndrome usingoral pilocarpine. While there has been recovery from the dry eyesyndrome, the oral administration of pilocarpine has not been withoutside effects. Further, such oral administration implicates the entirebody in an effort to secure an effect in the eyes. A treatment usingAChE inhibitor decreases the tear breakup time (tears stay on the eyelonger) without side effects. This invention can reverse the process ofold age dry eye syndrome by reactivating the meibomian glands, whichsupply the oil components to basic tears.

The method of the present invention further provides a treatment methodfor hyperopia. As described elsewhere, AChE inhibitor restores readingvision in presbyopic patients and increases the accommodative amplitude.The disease hyperopia (farsightedness), maybe prevented by increasingthe amplitude of accommodation in the young hyperopes.

The method of the present invention further provides treatment formyopia. Several myopic presbyopics have also noticed a shift in distancecorrection towards hyperopia or a reduction of their myopia after AChEinhibitor treatment. Therefore, it is believed that treatment with AChEinhibitor can be a treatment to prevent and reverse the disease myopia.

The method of the present invention further provides treatment foramblyopia. Medical dictionary defines amblyopia as “dimness of visionwithout detectable organic lesion of the eye”. By using AChE inhibitorpatients can notice an increase of image size after treatment. Theirnon-dominant eye sees better than their dominant eye. Thus, AChEinhibitor treatment can be used in accordance with the present inventionin relative or absolute amblyopics to improve inherent weakness bymagnifying image.

The method of the present invention further provides treatment forglaucoma. It is known that there is an age correlation between the mostcommon variety of glaucoma (open angle glaucoma) and presbyopia. Thereare glaucoma agents that actively stimulate the ciliary body to achievepressure reduction in glaucoma. However, there are theories that duringthe treatment for glaucoma, lens proteins disintegrate and/or theciliary body secretes proteins abnormally (pseudo exfoliation syndrome).But by keeping the ciliary body active as in the treatment of presbyopiacan keep pressures at a normal level without needing shock therapy tothe ciliary body as in high doses of glaucoma medicines. By keeping thelens active as in treatment of presbyopia prevents the ciliary body fromabnormally secreting and prevents the disintegration of lens proteins.

The method of the present invention still further provides treatment forcataracts. It is known that there is an age correlation of presbyopiaand cataract formation. Currently, AChE inhibitor (PHOSPHOLINE IODIDE)is being used to treat glaucoma and accommodative estropia and theanterior sub capsular cataract formation is a side effect of prior arttherapeutic doses. For three years, there was no cataract formation inthe treated eye versus the non-treated eye. By practicing the method ofthe present invention, one can keep the lens flexible throughaccommodation. This will prevent the disintegration of lens proteins(cataract formation). To prevent cataract formation in both eyes, AChEinhibitor should be applied to both eyes. Simply by practicing themethods disclosed herein during the course of last three years, it hasbeen found that, there was no disintegration of lens proteins andcataract formation in the treated eye as opposed to the non-treated eye.

By practicing the method of the present invention, alleviation ofdiminished visual acuity due to, for example, macular cyst, macularhole, solar retinopathy, diabetic retinopathy, branch retinal veinocclusion and AMD can also be achieved. By “restoration or alleviationof diminished visual acuity”, it is meant that any significantimprovement in vision of a patient suffering from blindness or poorvision.

These diseases in human patients are usually diagnosed byopthalmologistis or other physicians familiar with etiology of eye, bymeans of special photography of the retina. In a typical diagnosticprocedure, flourecein angiography, the physician injects a fluoresceinvegetable- base dye into a patient's blood. The patient's pupil is alsodilated by administering pupil dilating drugs (mydriatic) to the eye.The physician then takes a series of photographs of the retina, using alight source at a particular excitation wavelength so that it causes anyleakage of fluid of the drug from the patient's retinal and choroidalvasculature to emit fluorescent light at a different wavelength. Thephysician then analyzes the series of photographs of the retina todetermine the presence and concentration of leakage. If present atabnormal levels as determined a physician skilled in this area, theseabnormal levels of fluorescent leakage indicate the presence or onset ofa particular retinal or choroid vascular disease.

By practicing the method of the present invention, the disease conditionof the yea is at least stabilized without further deterioration of thetissues.

The structure, cellular anatomy physiology, biochemistry and otherdetails of the eye are provided in various ophthalmological and medicalschool texts that focus specifically on the eye and diseases of the eyee.g. Dwanes Textbook of Ophthalmology, the American Academy ofOphthalmology Clinical Science Course, etc. The practicing physicians inthis art can readily determine anatomical structures of a normal anddiseased human eye whether the disease be in the anterior or posteriorregion of the eye ball. Once a human patient is diagnosed as sufferingfrom a disease such as those described in the above paragraph, an amountof a acetylcholine esterase inhibitor containing composition sufficientto provide a therapeutic benefit is administered.

Acetylcholine esterase inhibitors are known to one skilled in the art.There are at least two AChE inhibitor drugs currently approved forclinical use on the eye in the United States. They are (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate sold asPHOSPOHLINE IODIDE® (Wyeth-Ayerst, Philadelphia, Pa.), and physostigmine(also known as eserine) sold as ANTILIRIUM® (Forest Pharmaceuticals, St.Louis, Mo.). PHOSPHOLINE IODIDE is dispensed as eyedrops at a desiredpotency. PHOSPHOLINE IODIDE of various concentrations, such as forexample 0.25%, 0.125%, 0.06% and 0.03% and a pharmaceutically acceptablesterile diluent to dilute the concentrated form of this drug arecommercially available. PHOSPHOLINE IODIDE is currently used forglaucoma and accommodative esotropia. As such, PHOSPHOLINE IODIDE is nota preferred drug even to treat glaucoma and accommodative esotropiabecause of many adverse side effects caused by this drug when it is usedin the current regimen of multiple times a day at high concentrations.Some of the side effects known to be caused by the currently recommendeddoses of this drug (for glaucoma at 0.12 and 0.25 BID) are iris cysts,cataract formation especially anterior subcapsular, posterior synechiaeand elevated intraocular pressure.

In the new method, the cholinesterase inhibitor, such as phospholineiodide, administered in concentrations many fold more dilute thancurrently available pharmacological preparations, applied to the eyebefore sleep will achieve alleviation of the deteriorated ordeteriorating vision with none of the unacceptable side effects of theusual pharmacological preparations and without the loss of peripheralvision. The effect of one administration of the inhibitor can last formany days. The present invention shows that the effective concentrationof AChE inhibitor in the composition to treat diseases associated withthe posterior region of the eye can be very low (for example, as low asat least 0.001% to about 0.0075% of PHOSPHOLINE IODIDE) to be effective.The invention discloses that such a concentration is extremely usefulmedically. Specifically, this lower dose range is especially useful inproviding eye drugs that will contain a concentration of AChE inhibitorthat is low enough to be both safe and effective. For example,application of a drop of 0.03% PHOSPHOLINE IODIDE followed by a drop ofsuitable diluent (e.g., artificial tear) is not incompatible with thedrug.

The composition administered to the eye should have a pharmaceuticallyacceptable carrier and a selected AChE inhibitor suspended or dissolvedin the carrier. The concentration of AChE inhibitor in the compositionadministered to the eye and the method of administration of thecomposition in accordance with this invention depends on the type ofAChE inhibitor containing composition used for therapy. For example,preferred concentrations of PHOSPHOLINE IODIDE in the PHOSPHOLINE IODIDEcontaining composition are from about 0.25% to about 0.001%. Morepreferred PHOSPHOLINE IODIDE concentrations are from about 0.15% toabout 0.005%. Most preferred PHOSPHOLINE IODIDE concentrations are about0.12%, 0.03% and 0.0075%. It is preferred to apply PHOSPHOLINE IODIDEtopically to the eyes in the form of eyedrops. Although it is preferredthat these solutions with various concentrations of PHOSPHOLINE IODIDEare stored in a refrigerator, they an be stored at room temperature forabout two months or even beyond two months without losing their efficacyto restore near vision in presbyopic patients.

A solution containing chlorobutanol (0.55%), mannitol (1.2%) boric acid(0.6%) and exsiccated sodium phosphate (0.026%) can be used as a carriersolution and/or as a diluent for PHOSPHOLINE IODIDE. While this solutionis presently sold as a diluent in the kit containing PHOSPHOLINE IODIDE,other pharmaceutically acceptable carriers or excipients that are knownto enhance membrane permeability and cellular uptake of the drug can beused as diluents with or without modification for application to theeye. Such carriers are known to one skilled in the art.

In a preferred embodiment of the invention, the AChE inhibitor isadministered at bedtime. A single topical application of a given AChEinhibitor at bedtime can enhance visual acuity in the phakic emmetropicpatients as well as in pseudophakic patients for a few days. Forexample, application of one to two drops of PHOSPHOLINE IODIDE of aselected concentration at bedtime can alleviate the diminished vision ofthe patients for at least five days. Preferably, the following steps arefollowed every time AChE inhibitor is applied to the patient. The firststep is to read for about 30 minutes. The second step is to administeran AChE inhibitor of a selected concentration. The third step is tosleep. Without wishing to be bound by any theory or explanation, it isbelieved that the reading for about 30 minutes preconditions eye musclesand visual pathway to respond better to the AChE inhibitor treatments.It takes about 6 to 8 hours of sleep to notice the restoration. If oneis awaken in the middle of sleep, the individual may notice partialeffect but after 6 to 8 hours of sleep the effect will be maximized. Bythe term “bedtime” it is meant that the time when the patient goes tosleep for about 6 to 8 hours, regardless of whether it is during the dayor night time. The composition is administered at bedtime, i.e., it isadministered just before the patient goes to sleep for about 6 to 8hours.

AChE inhibitor can be administered to the eye with the disease. Itshould be noted that the method of this invention can be successfullyused to treat diminished visual acuity in phakic as well as pseudophakicpatients. The method can also enhance visual acuity of an individual whohas no iris. Of particular interest is that this method can besuccessfully used to treat patients with artificial and rigidintraocular lenses (IOL's). IOL's are inserted at the time of cataractsurgery and in refractive procedures to make an individual emmetropic byclear lens extraction. Further, it should be noted that the diminishedvisual acuity can occasionally be alleviated also in contralateral eye(or untreated eye) to some degree.

Accordingly, by practicing the present invention, one can achieve adefinite, measurable gain in visual acuity in patients with retinalvascular or choroidal vascular disease or other known diseases ofposterior segment of the eye when administered with theacetylcholinesterase inhibitor, in the dilution and the manner outlinedabove. Increase in visual acuity can be measured by techniques wellknown to those skilled in the art. Although the mechanism of action isunknown, it is believed that a suitable dose of AChE inhibitoradministered at bedtime may allow the eye to accumulate sufficientstockpiles of acetylcholine by inhibiting acetylcholine esteraseactivity in the eye and strengthen the eye muscles leading to the normalperfusion of the blood to the posterior region of the eyeballparticularly choroid blood vessels. Retinal and choroidal function andhealth are dependant on normal perfusion of these tissues.

The method of the present invention also provides for treatment andprevention of congenital and acquired color vision blindness. Colorvision is made possible by the cones of the retina, which are alsoresponsible for central vision or best visual acuity. Color vision ismeasured by using standardized color plates, as in ISIHARA color plates.

In acquired color vision loss, as in retinal diseases such as StargardsDisease, juvenile macular degeneration, color vision can be restored inboth eyes by a drop of AChE inhibitor in only one of the color-blindeyes.

In patients with senile macular degeneration, there can be loss of colorvision together with the loss of central vision. Color vision loss willprecede or coexist with central vision loss. In Stargard's Disease,color vision loss may precede central vision loss by several years. Indry senile macular degeneration and diabetic retinopathy, color visionloss precedes and coexists with central vision loss. Patients complainof vision diminution. Color vision may be markedly decreased, althoughcentral vision has dropped slightly. Loss of color vision is a bad sign,as it represents diffuse or widespread damage of the cones. Color visionloss portends more central vision loss. Finally, with advanced disease,visual acuity <20/400, color vision may be maximal only up to 30percent. The exception to this rule is loss of vision with macularhole-formation. These patients may have very reduced visual acuity, butcolor vision remains normal. Macular-hole disease represents focaldamage of the central macula, the fovea. The para-foveal regions remainwith healthy cones for color vision at 100 percent.

Application of a drop of AChE inhibitor 0.015% can restore color vision.The mechanism of action is unknown, but AChE inhibitor probably worksdirectly on deenervated damaged cones to reenervate them. Thecolor-blind cones appreciate color again, and this improvement in colorvision correlates with improved visual acuity. This process reverses theprocess of juvenile and old age color blindness of the eye.

The method of the present invention also provides the treatment ofocular hypertension and glaucoma. Ocular hypertension is elevatedintra-ocular pressure without optic nerve damage and blindness. Theciliary muscle controls the outflow of aqueous humor of the eye,preventing the build up of intra-ocular pressure (IOP) in the eye(glaucoma). When AChE inhibitor 0.03% is given to patients with glaucomapreviously controlled with glaucoma drops (e.g. timoptic, alphagan, orxalatan), patients can be equally well controlled by less frequentadministration of AChE inhibitor (0.03% of AChE inhibitor drops). Whenapplied twice a week, as compared to daily or twice daily of the othermedications, there is equal control of the IOP. There is no progressionof the glaucoma as documented by no further damage to the optic nerve orloss of visual field.

There are distinct advantages to this new method in terms of compliance,tolerance, and economy. It is documented that the compliance of patientto take medications goes up with the fewer times the medication needs tobe taken. It is also understood that there is less tolerance, or loss ofeffect of a medication, when the medication is taken infrequently. Thereis more tolerance of other glaucoma medications because they are takenso frequently. Lastly, the fewer the times a medication is used, themore cost effective the medication will be. AChE inhibitor has been usedfor many years, up until recently, to treat glaucoma. However, frequenthigh dosing has led to unacceptable patient compliance and to lack ofefficacy (tolerance).

What is claimed is a new method for treatment of glaucoma, which wouldallow weekly and biweekly dosing. Generally, IOP elevation has nosymptoms and cannot be internally monitored by the patient. However,presbyopic patients taking AChE inhibitor notice that their needs foraccommodation enhancement comes on the fourth day or at about the sameday the intra-ocular pressure begins to be elevated. They can monitortheir ciliary muscle function through accommodation and thus indirectlythey can monitor their IOPs.

The method of the present invention also provides for the prevention ofthe progression of myopia. When given to several patients withprogressive myopia, the progression of the myopia was prevented. Byprogressive myopia is meant the progressive increase in glassprescription nearsightedness by 0.5-0.75 diopters in less than 1 yeartime for over three consecutive years. The mechanism for myopicprogression is unknown and has genetic and environmental influences. HowAChE inhibitor effects the prevention of progression of myopia isunknown. What is known is that myopic patients frequently haveabnormally large pupils versus the average patient. Young (20 yr old)myopic patients, having undergone RK or Lasik, may have as pooraccommodation function as the 40-year-old presbyopic patient.Biochemically, acetylcholine governs both the pupil size andaccommodation. Empirically, you may reason that an endogenous lack ofacetylcholine in the eye may be a cause for myopia. The presentinvention allows for higher levels of acetylcholine indirectly by AChEinhibitor.

The method of the present invention also provides for the treatment ofstrabismus or squint. AChE inhibitor also effects the external musclesof the eye or extra-ocular muscles (EOMS). The two eyes are held incheck on a straight line by fusion, which is a function of the strengthof the EOMs. Abnormal eye position, whether eso or exo (in or out) orhyper or hypo (up or down), is measured in prism diopters. The eyemuscles (EOMs) keep the eye aligned and have a potential strength inkeeping alignment. These measurements of fusional amplitude are alsomeasured in prism diopters. Measuring fusional amplitudes in presbyopicpatients before and after treatment of the presbyopia shows an averagegain of 5-10 prism diopters horizontally and 1-2 prism enhancementvertically. Diplopia or double vision occurs when an acquired paralysisof an EOM occurs. Whether exo, eso, hyper, or hypo, these misalignmentsof the eye are measured in prism diopters. When treating patients with aparalytic muscle with AChE inhibitor, the amount of the deviation isreduced on the first day of treatment versus the pretreatmentmeasurements. The fact that the enervation of the EOMs is throughacetylcholine and that paralytic EOM muscles become hypersensitive toacetylcholine concentrations accounts for the reason AChE inhibitorworks here.

The method of the present invention also provides for the potentiationof best visual acuity. AChE inhibitor also has the effect of makingnormal vision hyper or super normal, i.e., the base line normal vision(the best corrected vision) or seemingly perfect vision is potentiatedafter the treatment with AchE inhibitor. When normal patients with 20/20best corrected or uncorrected vision are given AChE inhibitor as inpresbyopia, best visions may improve to better than 20/20 or 20/15 to20/10 vision. This mechanism of action may be through a magnificationeffect of the crystalline lens of the eye. Some patients report amagnification of image in the treated eye versus the non-treated eye.This hyper effect is also seen in pseudophakia, where the crystallinelens has been replaced by an IOL intraocular lens. The mechanism may beexplained on this potentiation on the retinal tissue itself. The retinahas a conglomeration of ganglions and neurons, which communicate witheach other through acetylcholine and their actions are potentiated byAChE inhibitor.

The method of the present invention also provides for the phenomenaknown as neuro-protection. The recent literature is full ofpharmaceuticals that may protect the nerves of the eye in glaucoma e.g.the optic nerve and the neurons leading into the optic nerve or nervefiber layer. The agents that cause neuro toxicity or retinal toxicity ofthe eye are ischemia, or poor perfusion of blood flow, and poisons.Poisons are exogenous like alcohol or tobacco or endogenous as inStargards Disease or Congential Lebers Amaurosis and RetintitisPigmentosa. The endogenous poisons are genetic or bad gene related.

Whether ischemia or toxin, the final blow to nerve preservation is atthe neural synapses or connections between individual nerves. In theeye, acetylcholine governs 99% of synaptic connections between neuronsand may become sacrificed by ischemia and toxins. However, AChEinhibitor allows protection of synaptic spaces as it's nicotinicproperties allow for the excess acetylcholine to keep the nerve functionworking and also to repair potentially damaged synapses and restore andprevent loss of color vision, central visual acuity and peripheralvision. The muscanic properties of AChE inhibitor and its effect on thesmooth muscles of arterioles allows for the relaxation of arterioles,relief of ischemia and better perfusion of eye tissues, further assuringneuro protection. In Stargards Disease, the neuro-protection occurs whenthe AChE inhibitor interferes with the activity of the endogenouspoison. For example, one patient with deteriorated central and colorvision noticed that when using AChE inhibitor on a weekly regimen, therewas a reversal of the improved central and color vision toward the endof the fourth day. Giving AChE inhibitor every 4^(th) day allowedneuro-protection of the visual pathway with out the cascading loss ofbest visual acuity and color vision. In macula degeneration and diabeticretinopathy, AChE inhibitor improves visual acuity and color vision andprovides neuro-protection to further visual loss. Patients are stronglyrecommended to use their medications but because of the age of many ofthe patients sometimes they stop or forget to take their meds with theloss of this neuro-protection. Their visions can be improved whenbeginning their medications but sometimes not to the degree of theoriginal improvement.

The present invention also provides for the treatment visual aberrationssecondary to pupil dilation. The pupillary constriction is by the actionof AChE inhibitor on the sphincter muscle of the iris, another intraocular muscle. Patients suffering from traumatic mydriasis (surgical ornon-surgical), subluxed intraocular lens, IOL, and central cornealopacities are improved with mild miosis that is sustained with AChEinhibitor. Many patients with myopia, (before and after Lasik) sufferwith myopic nocturnal mydriasis and patients with psuedophakia (statuspost cataract extraction with IOL) complain of difficulty with nightvision especially while driving a motor vehicle. They also get relieffrom these vision problems after the application of AChE inhibitor.Pilocarpine is unacceptable because of the acute non-sustained miosis,which is accompanied with change of refraction and blurring of vision.

The topical administration of acetylcholine esterase inhibitors areapplied to one or both eyes depending on the type of treatment. For thetreatment and prevention congenital and acquired color vision blindness,treatment of ocular hypertension, glaucoma and progressive of myopia andpotentiation of best visual acuity it can be applied in one or botheyes. For the treatment of strabismus or squint acetylcholine esteraseinhibitors should be applied to the eye with paralysis of muscle. Forachieving Neuro-protection acetylcholine esterase inhibitors should beapplied to the eye in need of neuroprotection, and for treatingaberrations secondary to pupil dilation, acetylcholine esteraseinhibitors should be applied to the eye with the dilated pupil. Colorvision blindness, ocular hypertension, progression of myopia Strabismusor pupil dilation are referred to herein as disorders.

EXAMPLES

The examples below are carried out using standard drug administrationtechniques, that are well known and routine to those of skill in theart, except where otherwise described in detail. The examples areillustrative, but does not limit the invention. These examplesillustrate among other things (1) the alleviation of diminished visualacuity in humans suffering from diseases or disorders of the anteriorand/or posterior segment(s) of the eye and (2) potentiation of baselinenormal vision by topical administration of an AChE inhibitor to the eye.

1. Treatment of Emmetropes with Presbyopia

After a comprehensive examination of patients, seven emmetropes withpresbyopia were identified for the treatments. The mean age of thepatient was 48.5 years. These emmetropic patients were treated with(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioatesold under the trademark PHOSPHOLINE IODIDE. Each time only one drop ofone of the three different doses of 0.12%, 0.3% and 0.0075%concentrations were topically applied to the non-dominant eye of eachpatient. Patients were administered medication to the non-dominant eyeat bedtime after reading for 30 minutes. The treatment was repeated atfive to seven day intervals.

Pre-treatment uncorrected near vision was 20/50 to 20/70 and meanpre-treatment amplitude of accommodation was 2.5 diopters. Examinationof patients on days one to five showed considerable increase in nearvisual acuity from 20/20 to 20/25. The amplitude of accommodationimproved to 2.5 times. On the first day after the treatment, patientsnoticed a slight decrease of light sensitivity in dull illumination.This sensitivity subsided by the following day. There was a sustainedaccommodative effect from the first five days even though there was sometapering of the effect on day six or seven. Even on day seven, theamplitude of accommodation was significantly greater (1.5 times) thanthat of day zero. Near vision was restored in this manner without majorside effects. Patients noticed that they regained the ability to threada needle, suffered less computer strain and experienced fewer headaches.Patients could read newspaper print without corrective lenses for nearvision.

2. Treatment of Patients with Age Related Macular Degeneration, MacularCyst, Macular Hole, Solar Retinopathy, Diabetic Retinopathy, BranchRetinal Vein Occlusion, or Lebers Congenital Amaurosis

Twenty nine patients (34 eyes) were studied with ages 42 to 92. Etiologyvaried from diseases of the choroidal vasculature such as dry AMD andwet AMD, macular hole, Solar Retinopathy, Lebers Congential Amaurosisand retinal vascular diseases such as Diabetic Retinopathy withMaculopathy, and Retinal Vascular Occlusion. All of the patients studiedshowed restoration of vision. Patients included both phakic andpseudophakic. Medications were applied similarly at bedtime after about20 minutes of reading once a week. Patients monitored their visions andif there was a regression of vision midweek, the dose was made twiceweekly. A drop of PHOSPHOLINE IODIDE at a concentration of 0.03% with orwithout a drop of an artificial tear as a diluent was the regimen. Twopatients stopped their medications and lost the effect (patient 5 and9). One patients began using the medication in the morning and likewiselost the effect (patient 12). Another patient (patient 14) administeredthe drug at dinner time and lost the effect. These four patients hadtheir visions restored on restarting the medications at bedtime afterreading for about 20 minutes. The vision restoration is immediate andgenerally noticed on the first day or week of treatment. The medicationwas given unilaterally, that is to the diseased or more diseased eye.Most patients showed a constriction of the pupil in both eyes althoughthe medication is given in only one eye. Pupil constriction is notnecessary for vision improvement, as seen in patient 29 who is aniridic(no iris). Occasionally, patients noticed an improvement of vision alsoin the opposite or contralateral eye. That is, patients with bilateraldisease, when the poorer of the two eyes is treated, the untreatedbetter eye can show an effect of vision improvement. All patients weregiven pre treatment comprehensive examinations and had documentedretinal and/or choroidal vascular disease by flourescein angiography.

Patient 1: This patient was pseudophakic and diagnosed as suffering fromwet AMD. Prevision was counting fingers (CF), pinhole vision no help(PHNH). At one foot, vision was 1′/400. On day one, vision improved to1′/100 or to 3′/400. At one week vision was 6′/400 and at two weeks20′/300. At 8 weeks, distant vision was 20/400, 20/300 and near vision20/70. At 3 months vision was 20/200−1.

Patient 2: This patient was pseudophakic and diagnosed as suffering fromdry AMD. Prevision 20/40−2 PHFH. At one week 20/30 ph 20/25. At 8 weeksvision was 20/30−.

Patient 3: This patient was pseudophakic and diagnosed as suffering fromretinal vascular occlusions. Prevision CF PHNH 3′/300. At one weekvision improved to 3′/70. At week two vision was 3′/25 or 6′/400 andnear vision 20/70.

Patient 4: This patient was pseudophakic and diagnosed as suffering fromdry AMD. Prevision 20/70− near vision 20/40. At one week vision improvedto 20/50−1 near vision 20/25. At two weeks vision was 20/40−. At 4 weeksvision was 20/40−2, near vision 20/25.

Patient 5: This patient was pseudophakic and diagnosed as suffering fromdry AMD and preretinal fibrosis. Prevision was 20/50−2. At one weekvision was 20/40 PH 20/30− and at two week 20/30. At 8 weeks visionremains 20/30. At 3 months BK has stopped medusa for 10 days and visionwas 20/40−3.

Patient 6: This patient was pseudophakic and diagnosed as suffering fromdry AMD s/p laser for wet AMD. Prevision was 20/25+2. At one week vision20/20−1. At week three vision was 20/20−1.

Patient 7: This patient was pseudophakic and diagnosed as suffering fromearly or pre AMD. Prevision was 20/30+2. At one week vision was 20/25+1and at two week 20/20. At week four vision was 20/15−1. At three monthsvision was 20/20−1, near vision 20/20.

Patient 8: This patient was phakic and diagnosed as suffering from dryAMD. Prevision was 20/25. At one week vision was 20/20. At week twovision was 20/15−1.

Patient 9: This patient was pseudophakic and diagnosed as suffering fromdry AMD. Prevision was CF PHNH. At one week vision was 20/200. At twoweeks CF the patient stopped taking medications. At week three onmedications vision returned to 20/200. The patient admits to a markedimprovement of peripheral. At six weeks vision was 20/200 and nearvision 20/50.

Patient 10: This patient was phakic and diagnosed as suffering frommacular holes both eyes. Best vision was right eye 20/100 PH 20/100+1,near 20/70, left eye 20/100−1 PHNH., near 20/70. At one week right20/70− near 20/30, left 20/70−1 near 20/70. At three months vision was20/70−2 near uncorrected 20/50− right (last drop right was one week),left was 20/70−1 with a near uncorrected 20/30 (last drop was lastnight). Binocular near vision was 20/25− and patient is reading for thefirst time five years+.

Patient 11: This patient was pseudophakic and diagnosed as sufferingfrom diabetic retinopathy with maculopathy. Prevision was 20/70 PHNHnear 20/50. At one week no effect. At two weeks vision 20/40−1 near20/25. At six weeks vision remained stable at 20/40−1T.

Patient 12: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD. Prevision was CF PHNH or 1′/400. At one week vision was3/400, two weeks 6′/400 and at three weeks 20/300. For the next fourweeks the patient began using drops in the am. At 8 weeks vision was CFPHNH, 1/400′ snf and at 9 weeks 3/400. At 11 weeks vision was 6feet/200.

Patient 13: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD. Prevision was 20/100−1 PHNH near vision was 20/40−. Atweek one vision was 20/50−1 and near vision 20/25.

Patient 14: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD. Prevision was 20/100 PHNH. At one week vision was 20/50.At two weeks, vision was 20/40−3. The patient began using drops atdinner time and lost effect although pupil was constricted at week four.

Patient 15: This patient was pseudophakic and diagnosed as sufferingfrom wet AMD left eye and dry AMD right. Prevision was 20/40+ PHNH rightand CF PHNH 1′/400 left. At week one, vision was 1/100− with noticeableincrease in peripheral vision. The patient could read the time on hiswatch with the left eye. At week two, vision was 20/400+. (left eye)right eye at week one, vision was 20/30+1 and at week two, vision20/20−.

Patient 16: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD right and wet AMD left. Prevision was 20/25− PHNH right and20/200 PHNH. At one week vision was 20/20−2 right and 20/100 left. Atone month vision was 20/20−2 and 20/200 left.

Patient 17: This patient was phakic and diagnosed as suffering fromsolar retinopathy from staring into the sun. Prevision was 20/30+ PLNH.At one week vision was 20/25. At three weeks vision was 20/25 (no eyedrops for 8 days).

Patient 18: This patient was pseudophakic and diagnosed as sufferingfrom BRVO (Branch Retinal Vein Occlusion). Prevision was 20/400 PHNH. Atone week vision was 20/200 and at week two vision was 20/100−. Even atweek one, patient noticed a marked increase in vision. At week two,vision was 20/100 (slow) near vision 20/70.

Patient 19: This patient was phakic and diagnosed as suffering from milddry AMD right<left. Prevision was 20/20−1 right 20/25−3 PHNH left. Atone week left remained at 20/25−3 but at two weeks vision was 20/20−1left.

Patient 20: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD right<left. Prevision was 20/25−1, +1 right and 20/25−3left, PHNH. At one week left eye was 20/25 and as strong as the righteye. At week two vision was 20/20−1 and stronger than the right. At fourweeks both eyes were treated and vision was 20/20 right 20/20 left.

Patient 21: This patient was phakic and diagnosed as suffering fromLebers Congenital Amaurosis. Prevision was 20/CF or 6′/400 PHNH right,LP (light perception) left. At one week s vision was 6′/100 right and HM(hand motion). At week two, vision improved to 20/400 right, HM left. Atweek three, vision improved to 20/200−1 right, and remained at HM left.At six weeks vision was 20/200 with a near vision 20/70.

Patient 22: This patient was phakic and diagnosed as suffering fromdiabetic retinopathy. Prevision was 20/200right and 20/200 slow left eyePHNH. The weaker of the two eyes or left eye was treated. At one weekvision was 20/200 right 20/100−1 left. At week three both eyes weretreated and vision was 20/100 right, 20/100 left.

Patient 23: This patient was pseudophakic and diagnosed as sufferingfrom AMD and is status post visudyne laser. Prevision was HM handmotion. On the first day vision was 1′/400 and at one week 1′/100 and hereports a significant improvement of peripheral vision. At week threevision was 8′/400.

Patient 24: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD with prevision 20/40+ PHNH. At two weeks vision was 20/25.At two months the patient stopped meds and vision was 20/40. At 10 weeksvision returned to 20/25.

Patient 25: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD and occult wet AMD with prevision of 20/30+ PHNH. At oneday vision was 20/20− and this has remained through 2 months.

Patient 26: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD with prevision of 20/30−1+3 PHNH. At one day vision was20/20−2+3.

Patient 27: This patient was pseudophakic and diagnosed as sufferingfrom pre retinal fibrosis with a prevision 20/40− PHNH. At one dayvision was 20/40+ and at one week 20/25−2.

Patient 28: This patient was phakic and diagnosed as suffering frommacular hole right eye and mild dry AMD and early cataract left.Previson was CF 10/400 PHNH with near 20/400+ right and 20/30 PHNH. Near20/25 left. Medication was applied to the right only. At day one visionwas 20/400 right with near vision 20/100 in the right eye. The left eyeimproved to 20/20− at distance and 20/20 at near.

Patient 29: This patient was pseudophakic and diagnosed as sufferingfrom dry AMD right<left. The left eye has aniridia (NO IRIS). Previsionwas 20/30−1 PHNH no help right eye and 20/100− PH 20/70−1 left eye and anear vision of 20/70 left. The left eye was treated first initially. Atone week vision was 20/70− and at 4−wks 20/70. Both eyes were treatedand at two months vision was 20/25 right and 20/50 left. Near visionleft improved to 20/30.

3. Treatment of Patients with Loss of Color Vision

Patient AF 25 year old (yo) has been blind from Stargards Disease forfive years. The patient noticed that her color vision was changing atage 15 and preceded her blindness by several years. She was treated atthe Wilmer Eye Institute (John Hopkins University) and confirmed to haveadvanced color vision and central vision deficiency. When seen in ourclinic in May 2001, color vision was 0% OD (right eye), and 10% OS (lefteye). Central vision was 1/400 OD and 20/400 OS. After one drop of(0.015%) AChE inhibitor to the right eye color vision improved to 70% ODand 100% OS. At three months, best vision is 20/100−1 OD and 20/200 OSand s color vision is 90% OD and 100% OS.

Patient OJ with macular degeneration noticed a decrease in vision in theright eye (previously only the left eye was treated). Color vision ODwas 50% and central vision 20/40−. After one drop of (0.015%) AChEinhibitor color vision was 80% and central vision improved to 20/30.

Patient JL, 18 year old, has congenital color vision. Color vision was0% OU (both eyes). After one drop of (0.015%) Ache inhibitor, colorvision improved to 10% OD, 0% OS.

4. Treatment of Ocular Hypertension and Glaucoma

Patient Fr B who has hyperopia and glaucoma and who was treated withTimoptic XE every bedtime had no relief but when treated with 0.03% AChEinhibitor every 4^(th) bedtime, IOP (intraocular pressure) wasmaintained in the normal range, (<18), without evidence of progressionof disease. His hyperopia and presbyopia were also corrected on thisregimen and he could read at distance and near without glasses at theage of 64.

Patient HE has glaucoma and psuedophakia treated with alphagan twicedaily. When treated with AChE inhibitor (0.03%) every 4^(th) bedtime,IOP was maintained in the normal range. Best corrected vision improvedfrom 20/30, 2030 to 20/25, 20/25 (Potentiation of Best Visual Acuity).Night time vision while driving improved secondary to pupillaryconstriction (Aberrations Secondary to Pupil Dilation).

Patient CO has ocular hypertension as well as macular holes. Pretreatment IOP was 25 OD 24 OS. After treatment with AChE inhibitor(0.03%) for Macular holes, IOP was maintained in the normal range (<18).

5. Prevention of the Progression of Myopia

Patient KS, a 12 yo with progressive myopia for the past 3-4 years. Prevision was 20/100 OU uncorrected and with correction =2.50 best visionwas 20/20−. AChE inhibitor (0.03%) was given every weekend (Friday OD/Sunday OS, and uncorrected vision improved to 20/30− OU. Refractions atone year remained at −2.50 without progression of the myopia althoughthe patient went without her glasses seeing in the 20/30− range.

6. Treatment of Strabismus or Squint

Six presbyopic patients were tested for horizontral fusional amplitudesusing base out prisms and vertical fusional applitudes using base downprisms of the phoropter rotary prism. After AChE inhibitor (0.015%)fusional applitudes increased horizontally and vertically as statedabove. Patients admitted to less eye fatigue during and after drivingfor extended periods and while using the computer and performing theirusual daily activity. Their eyes ached less at the end of the day.

Patient D McD developed a paralytic strabismus in the right eye.Examination revealed a partial right medial rectus palsy. There was a XT(Exotropia) of 35 base in primary gaze, which increased to 50 XT on leftlateral gaze and reduced to ortho (no deviation) on right lateral gaze.AChE inhibitor (0.015%) was given to the effected right eye and the nextday the XT measured 20 base out prism in primary gaze.

7. Potentiation of Baseline Normal Vision

Patient GN is a 50 year old presbyopic with a best corrected previsionof 20/15−2, 20/15−1. After treatment with AChE inhibitor (0.015% or0.0225%), best vision improved to 20/15+3, 20/10−1.

Patient HM is a 70 year old with psuedophakia with best prevision of20/30+2. After AChE inhibitor (0.015%) best vision was 20/20+.

Patient FH is a 48 year old presbyopic with best corrected prevision20/15−1. After AChE inhibitor, (0.0225%) best corrected vision was20/15+2.

8. Treatment for Neuroprotection of Eyes

Patient 11, AV, is a 75 year old with Diabetic Retinopathy with a drymacula. Pre vision was reduced to 20/70. After 3 weeks with AChEinhibitor (0.015%) vision was 20/40. His eye was neuro-protected untilhe stopped his meds and vision dropped to 20/50−. Upon restartingmedications vision became 20/50+1 and has remained here at this level.

9. Treatment of Visual Aberration Secondary to Pupil Dilation

Patient MC had traumatic mydriasis after intra ocular and retinalsurgery. Pupil measured 8 mm in the eye versus 3 mm in the normal eye.After AChE inhibitor (0.015%) once weekly pupils were 4 mm and 3 mm andthere was less glare in the daytime and at night. The patient'sreferring ophthalmologist had put the patient on pilocarpine, whichneeded to be used 4 times daily to get relief from the visualaberrations.

Patient DB had large myopic pupils and is status post Lasik visioncorrection. Driving at night was still difficult from the glare andwhich problem was eliminated with AChE inhibitor (0.015%) once weekly.

Patient BB had psuedophakia with IOL subluxation. The patient complainedof distortion of vision, day and night from the edge of the IOL. Ratherthan reposition the lens, AChE inhibitor (0.015%) was given once weeklyto constrict the pupil over the edge of the optic of the IOL. Thepatient's vision became acceptable and another surgery was avoided.

While this invention has been described with reference to specificembodiments, those of ordinary skill in the art will understand thatvariations in these methods and compositions may be used and that it isintended that the invention may be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications encompassed within the spirit and scope of the inventionas defined by the claims.

What is claimed is:
 1. A method of treating a human patient sufferingfrom color vision blindness, the method comprising topicallyadministering to both eyes of the human patient or to an eye affectedwith said color vision blindness, an amount of a acetylcholine esteraseinhibitor containing composition sufficient to provide a therapeuticbenefit.
 2. The method of claim 1, wherein the composition isadministered at bedtime.
 3. The method of claim 2, wherein saidinhibitor is (2-mercaptoethyl) trimethylammonium iodide O,O-diethylphosphorothioate.
 4. The method of claim 3, wherein said(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis present at a concentration of 0.001% to 0.25%.
 5. The method of claim4, wherein the concentration of (2-mercaptoethyl) trimethylammoniumiodide O,O-diethyl phosphorothioate is 0.001%.
 6. The method of claim 4,wherein the concentration of (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is 0.0075%.
 7. The method of claim 4,wherein the concentration of (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is 0.015%.
 8. The method of claim 4,wherein the concentration of (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is 0.03%.
 9. The method of claim 4, whereinthe concentration of (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is 0.12%.
 10. The method of claim 4,wherein the concentration of (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is 0.25%.
 11. The method of claim 4,wherein the acetylcholine esterase inhibitor is contained in apharmaceutically acceptable buffer solution.
 12. A method forpotentiating best visual acuity in a human which comprises topicallyadministering to one or both eyes of the human an amount of acomposition sufficient to inhibit acetylcholine esterase activity in theeye of the patient.
 13. The method of claim 12, wherein the compositionis administered at bedtime.
 14. The method of claim 13, wherein saidinhibitor is (2-mercaptoethyl) trimethylammonium iodide O,O-diethylphosphorothioate.
 15. The method of claim 14, wherein said(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis present at a concentration of 0.001% to 0.25%.
 16. The method ofclaim 15, wherein the concentration of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate is 0.001%.
 17. Themethod of claim 15, wherein the concentration of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate is 0.0075%. 18.The method of claim 15, wherein the concentration of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate is 0.015%.
 19. Themethod of claim 15, wherein the concentration of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate is 0.03%.
 20. Themethod of claim 15, wherein the concentration of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate is 0.012%.
 21. Themethod of claim 15, wherein the concentration of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate is 0.25%.
 22. Themethod of claim 15, wherein the acetylcholine esterase inhibitor iscontained in a pharmaceutically acceptable buffer solution.
 23. A methodof treating of a human patient suffering from Strabismus, the methodcomprising topically administering to both eyes of the human patient orto an eye affected with said Strabismus, an amount of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate containingcomposition sufficient to provide a therapeutic benefit.
 24. The methodof claim 23, wherein the composition is administered at bedtime.
 25. Themethod of claim 24, wherein said inhibitor is (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate.
 26. The method ofclaim 25, wherein said (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is present at a concentration of 0.001% to0.25%.
 27. The method of claim 26, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.001%.
 28. The method of claim 26, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.0075%.
 29. The method of claim 26, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.015%.
 30. The method of claim 26, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.03%.
 31. The method of claim 26, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.12%.
 32. The method of claim 26, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.25%.
 33. The method of claim 26, wherein the acetylcholine esteraseinhibitor is contained in a pharmaceutically acceptable buffer solution.34. A method of treating pupil dilation in a patient which comprisestopically administering to both eyes of the human patient or to an eyeaffected with said pupil dilation, an amount of (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate containingcomposition sufficient to provide a therapeutic benefit.
 35. The methodof claim 34, wherein the composition is administered at bedtime.
 36. Themethod of claim 35, wherein said inhibitor is (2-mercaptoethyl)trimethylammonium iodide O,O-diethyl phosphorothioate.
 37. The method ofclaim 36, wherein said (2-mercaptoethyl) trimethylammonium iodideO,O-diethyl phosphorothioate is present at a concentration of 0.001% to0.25%.
 38. The method of claim 37, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.001%.
 39. The method of claim 37, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.0075%.
 40. The method of claim 37, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.015%.
 41. The method of claim 37, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.03%.
 42. The method of claim 37, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.12%.
 43. The method of claim 37, wherein the concentration of(2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioateis 0.25%.
 44. The method of claim 37, wherein the acetylcholine esteraseinhibitor is contained in a pharmaceutically acceptable buffer solution.